Allostatic Interoceptive Overload Across Psychiatric and Neurological Conditions

Emerging theories emphasize the crucial role of allostasis (anticipatory and adaptive regulation of the body ’ s biological processes) and interoception (integration, anticipation, and regulation of internal bodily states) in adjusting physiological responses to environmental and bodily demands. In this review, we explore the disruptions in integrated allostatic interoceptive mechanisms in psychiatric and neurological disorders, including anxiety, depression, Alzheimer ’ s disease, and frontotemporal dementia. We assess the biological mechanisms associated with allostatic interoception, including whole-body cascades, brain structure and function of the allostatic interoceptive network, heart-brain interactions, respiratory-brain interactions, the gut-brain-microbiota axis, peripheral biological processes (in ﬂ ammatory, immune), and epigenetic pathways. These processes span psychiatric and neurological conditions and call for developing dimensional and transnosological frameworks. We synthesize new pathways to understand how allostatic interoceptive processes modulate interactions between environmental demands and biological functions in brain disorders. We discuss current limitations of the framework and future transdisciplinary developments. This review opens a new research agenda for understanding how allostatic interoception involves brain predictive coding in psychiatry and neurology, allowing for better clinical application and the development of new therapeutic interventions

https://doi.org/10.1016/j.biopsych.2024.06.024 As a species, we regularly encounter a variety of environmental challenges, including infections, pollution, physical stress, socioeconomic disparities, and trauma.These factors influence our overall well-being (1).Our adaptive capacity is shaped by the intensity of these threats and our inherent biological predispositions (2).Moreover, this adaptation relies on different regulatory physiological mechanisms that anticipate, mediate, and respond to the complexity of environmental and biological interactions (3,4).These regulatory physiological mechanisms can foster successful resilience or result in physical, neurological, and psychiatric disorders (5).Although previous evidence has focused on how our biological systems respond to external stressors, leading to either adaptability or the emergence of diseases (6), significant gaps in our knowledge persist.
Emerging models could offer new perspectives.Recent studies have underscored the significance of anticipatory biological reactions to upcoming external challenges, or allostasis (13,14), and the perception, regulation, and modulation of internal states, or interoception (10,11,15,16) (Figure 1).Effectively coordinating anticipation of environmental demands and regulating internal bodily demands is crucial for adaptation.Conversely, dysregulation in this coordination is associated with psychiatric and neurological disorders.This dysregulation occurs when there is a mismatch between the anticipated energy expenditure and the actual energy required to cope with stressors, leading to physiological alterations due to overload (17)(18)(19).A deeper understanding of allostasis and interoceptive processes could elucidate the mechanisms that govern adaptability or vulnerability to psychiatric and neurological disorders (4,7,15,17,20), thereby offering an innovative framework for diagnosis, characterization, and intervention.
This review explores the allostatic interoceptive framework in psychiatric and neurological disorders, drawing on an extensive search of MEDLINE, Embase, and Web of Science databases for literature published from January 1, 1998, to June 30, 2023.The search utilized keywords related to external demands, biological processes, allostasis, interoception, and the disorders in question (see Supplemental Section S1).The review is divided into 4 main sections: 1) an overview of integrative models emphasizing allostatic interoception; 2) a detailed examination of allostatic interoceptive processes in disorders such as depression, anxiety, Alzheimer's disease (AD), and behavioralvariant frontotemporal dementia (bvFTD); 3) an analysis of the framework's role in elucidating neurological and psychiatric diseases across the life span, including its interaction with the spatiotemporal dynamics of brain function; and 4) a discussion of the research and clinical implications of this framework.
We anticipated empirical support for the presence of allostatic and interoceptive alterations in psychiatric disorders (mainly depression and anxiety) and neurological disorders (mainly AD and FTD).We also expected that these alterations would be associated with the core clinical features of these disorders.Additionally, we hypothesized that pathophysiological mechanisms within the allostatic interoceptive framework could help explain the neurocognitive and behavioral alterations that we observed.Finally, we elaborate on how the allostatic interoceptive framework interacts with complementary models to explain further normality and the emergence of psychiatric and neurological disorders.

ALLOSTASIS, ALLOSTASIS LOAD, AND INTEROCEPTION
Across the life span, humans face different environmental demands such as physical threats, air pollution, infections, and stress, as well as social determinants of health, including social disparities and adversities, which together are known as the exposome (21)(22)(23).In adaptative situations, exposomes activate physiological mechanisms to ensure survival and maintain internal equilibrium (14,24,25).Allostasis, which refers to the anticipatory and adaptive regulation of the body's physiological processes, is central to adaptation (13).Allostasis is modulated by different biological processes, including genetic and epigenetics, that impact cardiovascular, inflammatory, and metabolic functioning (11,13,14) (Figure 1 and Box 1).

THE INTEGRATED ALLOSTATIC INTEROCEPTIVE FRAMEWORK
The allostatic interoception framework refers to the anticipation and modeling of external demands based on perception, integration, and regulation of inner biological states.Allostatic interoceptive processes allow for the modulation of different biological processes that lead to adaptation or disease (15,16,20,26,57) (see Figure 1A).This framework is consistent with predictive coding, which states that the brain anticipates and models external demands based on internal cues and demands (16,20,58,59).A prediction error is generated when an anticipated modeled signal differs from the actual input.Prediction errors help refine future anticipations and adapt to new challenges (47,59).Discrepancies between predicted and actual signals can trigger dysfunctional responses (7,15,16,20,45,47,60).The Bayesian brain concept extends this idea, suggesting that the brain operates as a Bayesian inference machine, wherein priors-preexisting information, constraints, or knowledge biologically determined or learned (61)-are continuously updated with new sensory evidence to optimize perception and action (62).Thus, some biological priors, such as genetically encoded modulations or Box 1. Glossary Interoception: The process by which the nervous system senses, integrates, and anticipates bodily signals at both conscious and subconscious levels, providing a moment-to-moment mapping of the body's internal landscape.Interoceptive skills encompass sensitivity (accurate detection of internal bodily signals), awareness (ability to be conscious of internal sensations), and metacognition (ability to reflect upon, infer, and evaluate one's interoceptive skills), among other domains.Descending pathways play a crucial role in interoception by modulating these bodily signals through autonomic, endocrine, and immune systems, integrating higher brain functions with bodily regulation and maintaining homeostasis.Exteroception: The process of sensing stimuli originating outside the body.It encompasses the perception of environmental stimuli through sensory organs, enabling individuals to interact with their surroundings.Exposome: The totality of an individual's environmental physical (i.e., pollution) and social (i.e., socioeconomic conditions) exposures across a lifetime that impact health, including pollutants, diet, lifestyles, social determinants of health, social adversities, and structural inequalities.Allostasis: The process of achieving stability through change, wherein the body anticipates and generates biological plans to face future needs.An illustrative example of allostatic interoception is how the brain anticipates the need for strenuous activity and prepares the muscles by increasing blood flow.Allostatic load: The cumulative strain on the body that results from repeated cycles of anticipatory biological changes designed to prepare the body for potential needs and stress.These changes involve necessary energy adjustments that maintain the body's readiness for imminent biological responses.Allostatic overload: The amplified and dysregulated activation of anticipatory biological responses to potential needs, which lead to a state of wear and tear on the body.This increases the risk of amplified biological imbalances, which in turn trigger physical and psychological alterations.Predictive coding theory: A framework proposing that perception, cognition, and action are fundamentally influenced by the brain's predictive mechanisms.The brain continually creates, infers, and updates a model of the body and environment to anticipate sensory input.Predictions about incoming sensory information are continuously compared with actual sensory input to identify and minimize prediction errors.Through active inference, the brain reduces prediction errors through actions that align the environment with its predictions.High-order areas guide anticipation and predictions, and low-order areas guide perceptual processes.High-and low-order areas feed into each other to minimize prediction errors.The predictive allostatic interoceptive model: An active framework suggesting that the body anticipates and generates a model of the environment based on interoceptive inputs to face future needs and respond to external demands.Allostasis and interoception are crucial for maintaining physiological functioning and are believed to influence emotional, cognitive, and behavioral responses in humans.
developmental patterns (4), play a crucial role in shaping these predictions.
The integrated allostatic interoceptive processes are associated with brain structure and function of a set of areas known together as the allostatic interoceptive network (AIN) (47), which include the anterior midcingulate cortex, pregenual anterior cingulate cortex, subgenual anterior cingulate cortex, dorsal amygdala, ventral-anterior insula, dorsal midinsula, and dorsal posterior insula (47).Allostatic interoceptive processes are also determined by interactions between the heart, breath, and the gut-brain axis as well as by epigenetic, metabolic, autonomic, inflammatory, immunological, and microbiota mechanisms (16,44,47,63) (Supplemental Section S2).

THE INTEGRATED ALLOSTATIC INTEROCEPTIVE FRAMEWORK IN PSYCHIATRY AND NEUROLOGY
In psychiatry, a wide array of multigenic factors is recognized, but these are nonspecific due to pleiotropy (one gene linked to multiple traits) and cannot solely account for the onset of psychiatric disorders (67).Theoretical and empirical evidence instead points to complex interactions between environmental and biological factors as being fundamental to psychiatric diseases.Disruptions in anticipatory and regulatory mechanisms, particularly predictive allostatic interoceptive processes, are crucial in various psychiatric disorders, especially anxiety and depression.Evidence from interventions that target these processes further underscores their significance in the development of common psychiatric conditions (see Supplemental Section S4 and Figure 2) (68-73).

Anxiety
Anxiety is a complex emotional response encompassing fear, apprehension, and worry.It often arises in response to stress or perceived threats, whether real or imagined (74).Anxiety is an adaptative, natural human experience.When chronic or overwhelming, however, anxiety may interfere with daily functioning and lead to anxiety disorders (74).Anticipatory allostatic interoceptive processes are associated with anxiety symptoms and disorders (27,75).
Previous studies suggest heightened allostatic load in patients with anxiety disorders like panic and generalized anxiety (26).This encompasses increases in proinflammatory cytokines, sympathetic dominance, altered HPA axis function, and elevated biogenic amines during fear reactions (24,33,36).Dysfunctions in the anterior insula and anterior cingulate cortex, key regions for allostatic processing, have been tied to anxiety disorders (76).Allostatic overload manifests as symptoms like autonomic discharges in panic disorders, apprehensive anticipation, and somatic symptoms in generalized anxiety disorders (26,76,77).
Although the evidence is not yet conclusive (77), some studies have indicated brain-heart desynchronization, altered heartbeat evoked potential (HEP) index (77,79,82), and heightened cardiac and respiratory interoceptive sensitivity in anxiety ( 83) and obsessive-compulsive disorder (77,80,84).This increased sensitivity may predispose individuals to anxiety disorders by leading them to interpret typical cardiac and respiratory symptoms as catastrophic and triggering different anxiety symptoms.

Depression
Depression is a mental health disorder characterized by persistent feelings of sadness, anhedonia, depressive thoughts, motor alterations, tiredness, fatigue, changes in appetite and sleep patterns, and alteration of daily functioning (85).Previous studies have studied depression as an allostatic load disorder (15,17,45,46,86) marked by irregularities in various biological processes (87), including metabolic imbalances (88) with abnormal HPA axis activity, proinflammatory states (10), and skewed autonomic processes (45,46,86).Chronic stress, a primary driver of allostatic load and depression risk, induces changes in emotion-and memory-regulating brain structures like the hippocampus and amygdala (45,46).
Numerous studies have also indicated anomalies in interoceptive processing in depression, which often manifest as feelings of bodily disconnection or misjudgment of internal states (10,45,89).Evidence suggests altered interoceptive awareness in those patients (90)(91)(92).These interoceptive disturbances relate to emotion dysregulation and a negative attentional bias (93).Additionally, these deficits are correlated with structural and functional changes in the insula and other brain regions vital for interoceptive awareness (90,94).
Interoceptive changes can influence the allostatic system, contributing to depressive symptoms (45,46,95).Persistent ruminations and abulia have been linked to disruptions in cardiac and gastric interoceptive feedback, impacting anticipatory allostatic processes (45,46,94,95).Depression's hallmark symptoms, such as anhedonia and fatigue, are related to heightened body awareness, reduced body trust, and attentional issues (92,93).Recent reviews indicate that moderate to severe depression is tied to interoceptive alterations affecting decision making and emotion regulation, regardless of comorbidities or treatments like selective serotonin reuptake inhibitors (89).

Explanatory Models
The connections between the allostatic interoceptive framework and psychiatric disorders are primarily based on correlational studies (96), which are valuable in cognitive neuroscience despite potential confounders and challenges in reproducing causal models (96).Association studies support the framework's relevance in depression and anxiety.In depression, the locked-in brain hypothesis suggests inefficient energy regulation and insensitivity to prediction errors, leading to mood changes, reduced motivation, and difficulty engaging in activities (45).This is linked to changes in the subgenual anterior cingulate cortex, which regulates autonomic control and energy, contributing to depressive symptoms (45,97).Temporary changes in behaviors like eating, sleeping, or exercising can also lead to transient changes in energy regulation, thereby contributing to episodic depression (45).

PREDICTIVE ALLOSTATIC INTEROCEPTION IN NEUROLOGICAL DISORDERS
Studies of allostatic interoception in neurological conditions have been mainly focused on neurodegenerative disorders (Table 1; Tables S1 and S2).Allostatic overload can heighten sensitivity to future stressors, resulting in a state of hypervigilance (24).Such a state can induce chronic stress, leading to inflammation, metabolic imbalances, and increased neurotoxicity, which in turn can cause neural damage.Over time, these detrimental effects may contribute to cognitive and behavioral decline and raise the risk of developing dementia (8,24,102) (Figure 2).

Alzheimer's Disease
AD is a neurodegenerative disorder associated with genetic and preventable factors caused by the progressive accumulation of amyloid-b and tau proteins in the brain, leading to neuronal damage and brain atrophy (103).Clinically, AD is mainly characterized by deficits in episodic memory, language, visual-constructional abilities, praxis processes, and behavioral regulation in conjunction with classical brain atrophy affecting parietal, temporal, and hippocampal regions (104).
The prevalence of AD can be attributed to modifiable factors (105).These include socioenvironmental factors such as air pollution, deprived neighborhood conditions, and healthrelated factors such as chronic diseases (24,32,35,36,106,107).Such socioenvironmental risks are correlated with allostatic load and can trigger the dysregulation of physiological processes (24), as supported by previous studies (24,32,102,108,109).
Peripherally, AD is associated with dysregulation in the HPA axis, linked to glycemic alterations and insulin resistance (32).Elevated cytokine levels in patients with AD indicate chronic inflammation (115).Furthermore, changes in astrocytes and glial cells partially explain AD pathology (116).Altered heart rate variability and blood pressure, both autonomic processes, are related to predictive interoceptive failures (117).Accelerated epigenetic aging due to stress and changes in DNA methylation of inflammatory and metabolic pathways have also been reported in patients with AD compared with control participants (118,119).
Moreover, patients with AD exhibit disrupted interoceptive signal processing, which may contribute to symptoms from mood disturbances to reduced self-awareness (45,76,91).Compared with healthy control participants, patients with AD demonstrate reduced interoceptive awareness related to altered HEP modulations and abnormalities in the frontotemporo-insular network (113,120).Although the evidence is still being debated (111,121), individuals with AD tend to present impaired performance in interoceptive tasks, abnormal modulations of the HEP, and deficits in interoceptive awareness associated with behavioral problems like irritability and increased stress (121).

Behavioral-Variant FTD
bvFTD is a neurodegenerative disease marked by behavioral changes such as apathy, disinhibition, and empathy loss coupled with difficulties in language, executive functions, and motor impairments related to fronto-temporo-insular degeneration (122,123).Allostatic load (102) and interoceptive alterations have been identified as significant factors that affect the capacity of patients with bvFTD to reach appropriate responses to external demands (109,113,121).
Research indicates alterations in predictive allostatic interoceptive processes in bvFTD involving structural and functional degradation of the AIN and allostatic biomarkers (8,23,47,59,63,102,109,111,113,124).Resting-state studies have also shown disrupted connectivity in the default mode and salience networks, 2 networks intimately related to AIN (47).Allostatic interoception dysregulation in bvFTD associated with altered AIN functioning underlies the behavioral and cognitive disturbances observed in those patients, including apathy, disinhibition, sociocognitive and emotional deficits, and executive dysfunction (109,113,121).
Heart-brain interactions in bvFTD demonstrate modified HEP modulations, with reduced HEP during active tasks and ,10 articles in the field; 2) emergent: around 20 to 30 articles; and 3) robust: more than 30 articles.See Tables S1 and S2 for detailed studies.
Early axonal damage is indicated by elevated neurofilament light chain levels, which have been linked to other allostatic markers such as body mass index and cardiovascular biomarkers (37).

Explanatory Models
Allostatic interoception is intricately connected to neurodegeneration at multiple levels (59,109).Neurodegeneration disrupts the allostatic interoceptive system, affecting biological cascades that also affect the allostatic interoceptive mechanisms in a mutually deteriorating cycle (8,24,59,109).Additionally, a less-studied theory proposes that chronic stress may affect immune regulation, possibly playing a role in the development of FTD, TDP-43 protein aggregation (126), and other neurodegenerative conditions (127).

CONTRASTS BETWEEN THE ALLOSTATIC INTEROCEPTIVE PROCESSES AND OTHER MODELS OF DISEASE
The allostatic interoceptive framework offers a unique perspective compared with the diathesis-stress (128) and traditional homeostatic models (129).The diathesis-stress model links inherent biological vulnerabilities and external stressors to disorders, while the homeostatic model focuses on maintaining internal balance affected by predispositions and external factors.However, these models have limitations, such as in depression related to external stressors and sporadic AD (105) and in failing to account for dynamic biological responses to various exposures (14,130).
In contrast, the allostatic interoceptive framework emphasizes the dynamic interaction between biological factors and external threats based on internal sensing processes (17,47,64).This approach is consistent with enactive frameworks that view disease as changes in interactions between biological agents and the environment rather than merely as brain diseases (131).This enhances the understanding of multietiologic diseases from dimensional and transdiagnostic perspectives and helps to better explain altered cognitive and behavior patterns, consistent with frameworks such as the Research Domain Criteria and the Hierarchical Taxonomy of Psychopathology (Box 2).

NEW PERSPECTIVES OF THE ALLOSTATIC INTEROCEPTIVE FRAMEWORK IN PSYCHIATRY AND NEUROLOGY
The allostatic interoceptive framework opens new research avenues in psychiatry and neurology by examining how predictive allostatic interoception processes are crucial during critical neurodevelopmental periods.Alterations in these processes have been linked to conditions like autism (132), attention disorders ( (8,44,47,63,109).Current research highlights gaps, such as the impact of neurodevelopmental changes and external threats, on these mechanisms (Box 3).
The proposed framework also interacts with brain spatiotemporal dynamics, where different time scales affect interoception and cognitive processes (137,138).For example, in depression, altered time scale processing affects anticipatory and interoceptive functions, leading to symptoms like reduced speed in processing prediction errors (139).Similarly, besides the allostatic interoceptive failure in bvFTD (63,102,109,111), patients with bvFTD exhibit impaired brain temporal dynamics with 2-fold transient altered temporal states leading to slow (apathy) or fast (disinhibition) neural states (44).Moreover, conditions like autism and schizophrenia (140,141) show deviations in predictive oscillatory patterns that affect neural synchronization and responses to environmental challenges

Box 2. Biological and Clinical Dimensionality
The Research Domain Criteria (RDoC) brings a biological perspective to psychiatric disorders (151) and promotes primary constructs from genes to brain connectivity to self-report of behaviors (152).Allostatic interoception processes are linked to the framework proposed by RDoC.First, allostasis and interoception align with constructs assessed by RDoC, including those evaluating how humans react in the presence of harmful stimuli such as threats, stress, or fear (negative valence systems).Dysregulation in allostatic interoception can contribute to heightened emotional responses and maladaptive stress reactions, impacting negative valence systems.Although RDoC does not originally include interoception, recent studies have made such a claim for inclusion (54).Furthermore, allostatic interoception processes affect different biological and physiological pathways from genes to complex behaviors, which concur with the multilevel units-of-analysis structure of RDoC.Future studies could incorporate the study of allostatic interoception processes by following the RDoC structure, including multiple units of analyses (genes-to-complex behaviors) of processes critical for adaptation and disease.A deeper understanding of allostatic interoception could improve dimensional clinical models for psychiatric and neurological disorders.This approach aligns with the Hierarchical Taxonomy of Psychopathology framework (HiTOP) (153), which represents a significant paradigm shift toward dimensional and quantitative nosology of altered behaviors, echoing contemporary calls for broader transdiagnostic clinical characterizations.Both frameworks emphasize dimensional clinical characterization (8,111).A more profound understanding of the clinical patterns linked to various physiological pathways of allostatic interoception can enhance transdiagnostic and dimensional characterizations of psychiatric and neurological disorders.This approach is consistent with current advocacy for integrated frameworks, such as combining HiTOP and the RDoC, to foster a dimensional and transdiagnostic understanding of the clinical and pathophysiological pathways underlying brain disorders (12).(140,141) (Box 4).Despite the mentioned findings (140,141), current evidence on the role of an allostatic interoceptive framework on other disease models, including autism and schizophrenia, is still under debate (140,141).Future research should focus on generating contrastive and comparative studies on how the allostatic interoceptive framework and spatiotemporal approaches better explain the neurobiology and clinical manifestations observed in psychiatric disorders (for a further review of new perspectives of the allostatic interoceptive framework, see Supplemental Section S5).

DISCUSSION
The current scoping review highlighted the role of allostatic and interoceptive processes in integrating environmental and biological factors under normal and neuropsychiatric conditions.We gathered evidence showing how these processes are altered and directly impact clinical and neurocognitive profiles in depression, anxiety, AD, and FTD, as well as other neuropsychiatric disorders (see Tables S1 and S2).Our review provides support for a more comprehensive understanding of multilevel biological alterations observed in psychiatric and neurological disorders in this model, compared with other approaches, such as the diathesis-stress model.
Our review identified proposed pathophysiological mechanisms altered in allostatic interoceptive processes that contribute to psychiatric and neurological disorders.These include disruptions in energy regulation, unadjusted prediction processes, impaired generation of internal and external models in response to environmental demands, and altered brainbiological systems underlying allostatic interoceptive processes in the context of neurodegeneration.These alterations stem from regulatory processes determined by the AIN and disrupted energy regulation and predictive processes at various biological levels, leading to cognitive and behavioral changes associated with clinical repertoires in psychiatry and neurology.
Current findings recognize that allostatic interoceptive dysregulations are intertwined with the cognitive, affective, and Box 3. Allostatic Interoception Across the Life Span Environmental risks and experiences vary across life span stages (21).For example, environmental threats or social determinants of health, such as infections, attachment issues, neighborhood deprivation, difficulties with educational attainment, social adversities, and exclusion, are more impactful during childhood and adolescence (154).In contrast, stress and social isolation are more critical in adulthood or older ages.Differential environmental risks at various stages of the life span interact with the integrity and development of biological systems, leading to the adaptation of disease processes over time (28).Early childhood experiences are foundational in shaping stress management mechanisms.Brain areas essential for interoception, such as the insula and anterior cingulate cortex, undergo maturation during this period and are affected by stress processing (120).Experiences of trauma or persistent stress during childhood can alter these neural pathways, resulting in emotional and cognitive challenges in later life (28) that can create long-lasting interoceptive dysregulation.Physiological and emotional changes characterize adolescence.Pubertal hormonal fluctuations can influence interoceptive sensitivity and the body's response to stress (29).This stage is often marked by the emergence of mental health issues, with disruptions in interoceptive processing increasing vulnerability to mood-related disorders (136).Notably, disorders commonly diagnosed in childhood and adolescence, such as autism spectrum disorder (155) and attention-deficit/hyperactivity disorder (156), exhibit allostatic load and interoceptive anomalies (157).In adulthood, multiple stressors ranging from professional challenges to parenthood can affect interoceptive perceptions.Prolonged stress may intensify a person's perception of bodily sensations, contributing to somatic symptoms and pain-associated disorders (158).The wear and tear on the body due to constant stress adaptation contributes to neurological disorders and becomes increasingly evident with age (24,28,140,159).Moreover, early adversities are associated with increased allostatic overload in adulthood and older ages, as revealed by metabolic and autonomic alterations (159,160).In the later years, the cumulative burden becomes pronounced.Elevated allostatic load is linked to memory problems and impairment in executive function (27).Prolonged stress and increased allostatic load can deepen health issues such as cardiovascular disease and osteoporosis (160).Additionally, the compound effects of chronic stress and innate predispositions to neurodegeneration influence allostatic interoceptive processes, which are central to clinical symptoms in common dementias (75,160).

Box 4. Allostatic Interoception and Spatiotemporal Dynamics
Recent models of allostatic interoception have been linked with models of biological complexity and brain spatiotemporal dynamics (137).The interplay between external demands, interoceptive processes, and cognitive inputs favored by allostatic interoceptive processes requires complex spatiotemporal processing.Specifically, each type of input, interoceptive or exteroceptive, has its temporal rhythm and specific neural microstructures.For example, interoceptive inputs from the heart have a constant rhythm compared with exteroceptive environmental signals (152).Moreover, brain areas in the allostatic interoceptive network have intrinsic neural time scales at different sites because the prefrontal cortex manages longer time scales of processing than regions like the anterior insula (149).The complexity of prediction processes also involves different time scales; while prediction signals lean toward slower beta range oscillations, prediction errors lean toward faster gamma range oscillations (17).Today, how brain spatiotemporal dynamics interact with whole-body biological and physiological changes promoted by anticipatory allostatic interoceptive processes is unknown.Future research should integrate spatiotemporal analyses to study the complexity of the predictive allostatic interoceptive processes (63,137) and their relationships with different pathways.emotional symptoms of psychiatric (45,46) and neurological conditions (102,109,111).Core evidence in depression and bvFTD support this view.Depression has been described as a systemic dysregulation of the body's internal mechanisms in response to stress (90,93).Individuals with depression often display altered interoceptive processes.These alterations are associated with specific dysexecutive and emotional dysregulation in patients with depression (45,90).In bvFTD research, the alteration of allostatic interoceptive processes, as gauged by HEP modulation and altered connectivity in AIN, has been associated with executive dysfunction, behavioral disturbances, and impaired emotion and social cognition (102,109,111).
Temporary changes in allostatic interoceptive processes and their impacts on biological cascades could explain the episodic symptomatic phases of psychiatric disorders, particularly in the presence of intense external demands (142).
In contrast, in neurodegenerative disorders, a more chronic, persistent, and accumulated dysregulation of the allostatic interoceptive mechanisms that affect the biology-environment interactions is expected (8,59).These dysfunctions could affect other mechanisms, including oxidative stress processes, mitochondrial breakdown, and altered protein recycling and aggregation (2,8,34,37,63,102,143).The precise mechanisms that lead to neurodegeneration or the temporary imbalances observed in psychiatric conditions remain unclear.New studies are required to explore the potential biological and environmental mechanisms that trigger temporary or chronic changes in psychiatric and neurological conditions.

NOVELTY OF THIS STUDY
Current evidence on an allostatic interoceptive framework for psychiatry and neurology faces essential caveats.Although some studies have analyzed combined alterations in allostatic interoceptive processes associated with behaviors (8,59,64) and psychiatric (45,46) and neurological (8,16,63,102,109,111,144) disorders, most research has focused on interoceptive impairments or allostatic overload in isolation.With some exceptions (102,109,111), studies have also focused on specific disorders, lacking dimensional alterations observed in psychiatric and neurological disorders.The current study bridges these gaps by analyzing the relationship between allostatic interoceptive mechanisms and biological, neurocognitive, and clinical changes in psychiatric and neurological conditions.It transcends traditional categorical approaches, integrating dimensional frameworks in neuropsychiatry.It also shows how these processes evolve across the life span, impacting brain health, and interact with brain spatiotemporal dynamics.
New studies should implement specific metrics to capture allostatic and interoceptive processes in psychiatric and neurological disorders.These metrics should include allostatic load indices (27), which measure various biological levels affected by allostatic load processes, and assessments of interoception sensitivity and awareness (102,145,146).Assessments of brain activity related to interoceptive processes, such as the HEP and the AIN dynamics, and their interaction with other networks could reveal the role of integrated allostatic interoceptive processes in these disorders (45,109).This is consistent with recent calls for including interoception as a critical construct in neuropsychiatric disorders (54,134).
Evaluating multiple biological levels associated with allostasis and interoception will enhance the understanding of intervention impacts on reducing allostatic interoceptive overload (15).Nonpharmacological interventions focusing on respiration, body scanning, and relaxation techniques have shown promise in reducing allostatic interoceptive load, thus alleviating symptoms of anxiety, depression, and somatic issues (41,147,148).
Current studies have begun to explore the impact of spatiotemporal brain dynamics on regulating allostatic interoceptive processes (44).Different biological processes, including interoception, exteroception, and cognition, occur at varying spatiotemporal dynamics (44,139,149,150).New research could investigate spatiotemporal brain dynamics in altered allostatic interoceptive processes and associate these metrics with specific spatiotemporal brain patterns using whole-brain modeling and other relevant methods.

LIMITATIONS OF THE CURRENT FRAMEWORK
Our research underscores the significance of allostatic interoceptive processes in psychiatry and neurology, but significant challenges remain.Few studies have combined the effects of allostasis and interoception on these disorders, with most examining them separately.This has resulted in an understanding based largely on correlations, highlighting the need for comprehensive studies that focus on longitudinal interactions between the environment and biology.There is also a notable lack of multilevel analyses, causal modeling, and complexity approaches in existing research.

CONCLUSIONS
This review emphasizes the crucial role of allostatic interoceptive processes in managing responses to environmental and biological interactions, leading to adaptive or dysregulated outcomes in psychiatric and neurological disorders.We provide evidence of allostatic and interoceptive changes in conditions such as anxiety, depression, AD, and bvFTD.These changes can predict various physiological, neurocognitive, and clinical features across disorders.Advancing research in allostatic interoception is vital for developing more in-depth studies on its role in brain health and disease, leading to the implementation of new insights in clinical settings and personalized treatment strategies.

Figure 1 .
Figure 1.Allostatic interoception regulates environmental and biological interactions across the life span.The left panel outlines predictive allostatic interoceptive processes.The allostatic interoceptive system (A) is supported by the allostatic interoceptive network, which includes principal hubs such as the anterior midcingulate cortex (aMCC), pregenual anterior cingulate cortex (pACC), subgenual anterior cingulate cortex (sgACC), dorsal amygdala (dAmy), ventral-anterior insula (vaIns), dorsal midinsula (dmIns), and dorsal posterior insula (dpIns).The limbic cortices can be divided cytoarchitectonically into agranular regions that send prediction signals and (dys)granular regions that receive prediction error signals from the internal milieu, initiating psychological responses.Allostatic interoceptive processes, which are rooted in brain-body interactions including brain-heart, brain-respiratory, and brain-gut-microbiome systems, facilitate anticipation and guide responses to internal and external demands and threats, which may vary across the life span (B).Various biological predispositions can either dampen or amplify allostatic interoceptive processes, including the functioning of cardiovascular, metabolic, inflammatory, and stress-hormone systems (C).The degree of responses to external stimuli are influenced by genetic-epigenetic predispositions toward adaptive behaviors related to disease risks (D).Visuals in (A-C) are illustrative examples and do not represent actual data.GWAS, genome-wide association study.

Table 1 .
Degree of Evidence on Allostatic Interoceptive Frameworks, Allostasis Processes, and Interoception in Psychiatric and Neurological Conditions